DEVELOPMENT OF THERAPEUTIC GENOME ENGINEERING IN RARE GENETIC DISEASES
A disease is defined as rare when it affects <200,000 people in the US, or 1 in 2000 people in the EU. Although one rare disease may affect a handful of individuals, the opportunities to have an immediate clinical impact and generate new scientific knowledge make the study of rare genetic conditions greatly valuable and endlessly rewarding. To this end, genome engineering technology has emerged as a powerful tool in the study of rare disease and therapeutic development.
LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD)
LAMA2 in healthy muscle and Schwann cells stabilize the basement membrane and maintains muscle architecture and nerve myelination. LAMA2-CMD patients have mutations in the LAMA2 gene, leading to muscle degeneration and neuropathy. Despite considerable advances in our understanding of the pathophysiology of LAMA2-CMD, currently, there is no curative option.
We previously developed a CRISPR activation-based approach to postnatally upregulate a disease modifier gene Lama1, which is structurally and functionally similar to Lama2, in a mouse model (Kemaladewi, Bassi et al, Nature, 2019). These findings led to the overall hypothesis that targeted LAMA1 gene activation can serve as a mutation-independent approach for LAMA2-CMD.
We will test this hypothesis by performing a dedicated preclinical evaluation of efficacy and safety profiles of Lama1 upregulation in a severe LAMA2-CMD mouse model. In addition, we will bridge the translation of the strategy from mouse- to patient-relevant models and evaluate the effect of human LAMA1 upregulation on cellular impairments, including mitochondrial respiration, migration, and myelination. Successful completion of these experiments will pave the way towards the development of mutation-independent therapeutic interventions for LAMA2-CMD and potentially other muscular dystrophies.
Aim 1: To test the hypothesis that early intervention in the severe LAMA2-CMD mouse model prolongs life expectancy, improves disease outcomes, and avoids humoral and cellular immune responses.
Aim 2: To test the hypothesis that LAMA1 upregulation rescues bioenergetic impairment, migration property, and myelination defects in LAMA2-CMD patient-derived cells.